Anti-microbial phenyl 3-halopropargyl ethers

ABSTRACT

Anti-microbial phenyl 3-halopropargyl ethers which are prepared by condensing a phenol with a 3-halopropyne.

r i A U lllLCu D ldLCD a is ANTI-MICROBIAL PHENYL 3- HALOPROPARGYL ETI-[ERS Inventors: Jay Philip OBrien, lrvington; Albert Israel Rachlin, Verone, both of NJ.

Assignee: Hoffmann-La Roche Inc., Nutley,

Filed: May 28, 1969 Appl. No.: 828,731

Related US. Application Data Division of Ser. No. 485,904, Sept. 8, 1965, Pat. No. 3,489,805, which is a continuationdnpart of Ser. No. 433,209, Feb. 16, 1965, abandoned.

US. Cl. ..260/612 D, 260/609 E, 106/15, 8/94.1, 424/340 1 Aug. 22, 1972 Primary Examiner-Remand Helfin AttorneySamuel L. Welt, Jon S. Saxe, Bernard S. Leon, William H Epstein and George M. Gould 5 7] ABSTRACT Anti-microbial phenyl 3-halopropargyl ethers which are prepared by condensing a phenol with a 3- halopropyne.

1 Claim, No Drawings ANTI-MICROBIAL PHENYL 3-HALOPROPARGYL ETHERS CROSS REFERENCE TO RELATED APPLICATIONS This application is a divisional application of Ser. No. 485,904, filed Sept. 8, 1965 and now US. Pat. No. 3,489,805, which is a continuation-in-part application of Ser. No. 433,209, filed Feb. 16, 1965 and now aban- I cloned.

DETAILED DESCRIPTION OF THE INVENTION wherein X is halogen, i.e., chlorine, bromine iodine or fluorine and Y is a sulfur or an oxygen atom.

The halogen substituents on the phenyl group can be either chlorine, bromine, iodine or fluorine, preferably chlorine or bromine, and they can be the same or different and can also be the same or different than the halogen on the acetylenic carbon which is preferably iodine or bromine. Compounds answering to this description are, for example, 2,3-dichloropheny1 3- iodo-2-propynyl ether, 2,3-dibromophenyl 3-iodo-2- propynyl ether, 2,3-dichlorophenyl 3-bromo-2-propynyl ether, 2-chloro-3-bromophenyl 3-bromo-2-propynyl ether, 2,3-dichloro-l-(2-propynyl mercapto)- benzene and the like. Compounds of formula I wherein Y is an oxygen atom constitute a preferred class.

The compounds of formula I are useful as anti-bacterial and anti-fungicidal agents. For example, they are useful as disinfectants or sanitizers or they can be used a in human or veterinary medicine as medicaments especially in diseases caused by a wide variety of bacteria and fungi for which these compounds have shown a high inhibitory effect. More particularly, the compound 2,3-dichlorophenyl 3-iodo-2-propynyl ether has exhibited unusual broad spectrum anti-bacterial activity of extremely high potency against both Gram-positive and Gram-negative bacteria, for example, against Streptococcus pyrogenes 4, Diplococcus pneumoniae 6301, Staphylococcus aurius 209, Escherichia coli J and Salmonella typhosa.

In addition to the extraordinary activity against Gram-positive and Gram-negative bacteria, this compound shows an inhibitory effect on a variety of fungi such as Candida albicans, Tricophyton mentagrophytes, Microsporum audouini and aspergilli. Of particular importance is the unexpectedly high activity against the fungi Aspergillus niger, Aspergillus flavus and Aspergillus oryzae. 2,3-Dichloro-3-iodo-2- propynyloxybenzene, when tested against Aspergillus niger, Aspergillus flavus and Aspergillus oryzae in a modified Czapek media, produced 100 percent inhibition of growth at less than 5.0 p.p.m. This activity renders the compound particularly useful as an additive for the prevention of mildew in such things as fibrous materials, leather, textiles, wood, paper and the like. In this particular aspect of the invention the compound can be utilized, for example, as an additive in paints where it has been found to have a total inhibitory effect on the above-mentioned fungi when used in amounts of 1 percent by weight or less.

Various concentrations of the compound were incorporated into a polyvinyl acetate latex paint and an outside linseed oil paint. The paints were brush-coated onto both sidesof sheets of filter paper and air dried for 48 hours. One inch squares of the coated paper were place on modified Czapek media in petri dishes, inoculated with a spore suspensions of Aspergillus oryzae and incubated for 7 days at 28-30 C. Results of these tests were as follows:

TABLE I Conc., Percent by Growth on Zone of weight of paint Paint Paint Inhibition 2.0 Latex No Growth 5 mm. 1.0 Latex No Growth 1 mm. 0.5 Latex Trace 0 0.25 Latex Moderate 0 Control Latex Heavy 0 2.0 Oil No Growth 10 mm. 1.0 Oil No Growth 10 mm. 0.5 Oil No Growth l mm. Control Oil Moderate to heavy 0 One inch squares of vegetable tanned leather were immersed in alcohol solutions of 2,3-dichlorophenyl 3- iodo-2-propynyl ether and air dried. The treated samples were placed on modified Czapek media, inoculated with a spore suspension of Aspergillus niger and incubated for 7 days at 2830 C. Results were as follows:

Complete inhibition of growth on agar.

The compounds of formula I are useful as anti-bacterial and anti-fungal agents in preparations containing said compounds in admixture with a pharmaceutical organic or inorganic carrier suitable for local administration. They can be used, for example, as contact disinfectants or sanitizers, or applied topically to affected areas. As carriers there are used substances which do not react with the new compounds, for example, gelatin, lactose, starch, talc, vegetable oils, polyethylene glycols and other known carriers for medicaments. The pharmaceutical preparations may be, for example, in the form of powders, sprays, salves, creams or suppositories or in liquid form as solutions, e.g., tinctures, suspensions or emulsions. If desired, they may be sterilized and/or may contain auxiliary substances such as preserving, stabilizing, wetting or emulsifying agents.

A conventional pharmaceutical formulation such as a cream, tincture or the like containing 2,3-dihalophenyl 3-iodopropargyl ether of the type disclosed herein in amounts of about 1 percent or less by weight of the total formulation provides an effective anti-bacterial/anti-fungal composition for the treatment of inflammatory conditions amenable to topical therapy. An exemplary ointment composition (Cream Base A) incorporating 2,3-dichloro 3-iodopropargyl ether as the active ingredient can be formulated as follows:

Stearic acid, light mineral oil, Span 60, Nipagin and Nipasol were placed in a suitably jacketed kettle, melted and heated to 70 C. 2,3-Dichloro-3-iodopropargyl ether was then added with agitation. In a separate suitably jacketed kettle there was placed water, sorbitol and between 60 and the mixture heated to 70 C. The amounts of each of the various components are indicated in the table below.

The water phase was then added to the oil phase with agitation. The water was agitated for 5 minutes at 70 C. and then cooled to 50 and then cooled to room temperature with agitation. The ability of the above composition to inhibit various organisms in conventional microbiological tests is shown below.

The ointment preparation was dissolved in dimethylsulfoxide and diluted with water and incorporated into Sabouraud-Agar. At the desired concentration the agar was flooded with suspensions of Candida albicans and dermatophytes and incubated at 25 C. for 48 hours in the case of Candida and for 7 days in the case of dermatophytes. The minimum inhibitory concentrations (M.I.C.) are given in the following table.

TABLE III Activity of Ointments Containing 2,3Dichlorophenyl 3- Iodo-2-Propynyl Ether Against Bacteria and Fungi in Vitro Organism M.I.C. (pg/ml.)

T. Mentagrophytcs 0.1 M. Audouini 0.1 C. Albicans 1.0

ments are expressed as zone inhibition and radius inhibition in the following table.

TABLE IV Activity of Ointments Containing 2,3Dichlorophenyl 3- lodo-2-Propynyl Ether Against Bacteria and Fungi in Vitro Organism Zone of inhibition tmm.)

S. pyogenes 4 3.0 D. pneumoniac 6301 3.0 S. aureus 209 14.0 E. coli J 3.5 C. albicans 24.0

Compounds of formula I are accessible by a variety of methods. The novel ether compounds can, for example, be prepared by reacting the appropriate 2,3- dihalophenol with 3-bromopropyne in the presence of anhydrous potassium carbonate, isolating the propynyl ether which forms and thereafter halogenating the acetylenic hydrogen for example by treatment with the appropriate halogen in the presence of a strong base, e.g., sodium hydroxide. Alternatively in the case of iodine, the terminal acetylenic carbon can be iodinated by first forming the copper salt by treating a solution of a copper ammonia complex and thereafter iodinating the copper salt, for example, by treating with a mixture of potassium iodide and iodine. The above reaction can be suitably carried out in an inert organic solvent such as alcohol, acetone and the like. The reactions can be conveniently carried out at room temperature or above or below room temperature. However, it is preferred to operate at a temperature between about 0 C. and about 30 C. The end product can be readily recovered by any of the usual techniques such as filtration, evaporation, etc.

Alternatively the compounds of formula I can be prepared by directly condensing a 1,3-dihalopropyne with 2,3-dihalophenol or 2,3-dihalothiophenol respectively. The condensation is suitably carried out in an inert organic solvent in the presence of a base. The reaction temperature is not critical though it is preferred to operate at an elevate temperature suitably at the reflux temperature of the reaction mixture.

In another of its aspects this application relates to novel biocidally active nitrophenyl propargyl ethers and thioethers to methods and compositions for the control of microorganisms using these novel compounds which are highly toxic to microorganisms, particularly to fungi. More particularly, this aspect of the application relates to compounds of the formula wo ll wherein n is an integer from 1 to 5, R is hydrogen or halogen and Y is a sulfur atom or an oxygen atom.

Compounds of formula II wherein n is 1 to 2, Y is oxygen and X is halogen, especially bromine or iodine, constitute a preferred group. The 2,4-dinitro derivative is specifically distinguishable by virtue of its anti-fungal activity particularly against T. mentagrophytes and M. audouini.

The ethers of formula II can be prepared by reacting the appropriate nitrophenol with a propargyl halide, preferably propargyl bromide, in the presence of an acid acceptor in a manner similar to the preparation of the 2,3-dihalophenylpropargyl ethers described above. As an acid acceptor, one can employ any suitable base such as, for example, sodium hydroxide, sodium methoxide, alkali metal salts such as sodium carbonate, potassium carbonate, etc., bicarbonates, e.g., sodium bicarbonate and the like. The reaction is conveniently carried out in any inert solvent preferably a polar solvent. Suitable solvents are, for example, water, ketones, e.g., acetone, etc., alkanols, e.g., the lower alkanols, methanol, ethanol, etc., lower alkyl nitriles such as acetonitrile and the like. In the case of the dinitro compounds it is preferred to use bicarbonate as the acid acceptor in a strongly polar solvent such as acetonitrile or lower alkanol. The reaction temperature is not critical, though it is preferred to operate at an elevated temperature, suitably at the reflux temperature of the reaction mixture. However, the reaction can be carried out at lower temperature, i.e., room temperature or below. The reaction starts upon mixing the reactants and is ordinarily completed in about 5-15 hours. Upon completion of the reaction, the reaction mixture is cooled to precipitate the inorganic salt formed in the reaction. The salt is filtered off and the filtrate distilled to recover the nitrophenyl 2-propynyl ether. Halogenation of the propynyl ether can be readily accomplished by reacting with a hypohalite. The reaction is suitably carried out in an inert solvent such as, for example, water, ethers, e.g., dioxane, tetrahydrofuran and the like. The hypohalite can be added to a solution of the propynyl ether or dissolved in an appropriate solvent to which the hypohalite can be added or, alternatively, the hypohalite can be prepared in situ by adding halogen and a suitable base such as sodium hydroxide and the like. Alternatively, iodination can be carried out via the copper salt as described above. Compounds of formula II wherein R is halogen can be prepared directly by condensing a 1,3- dihalopropyne with the appropriate nitrophenol or nitrothiophenol respectively by procedure analogous to that described above.

The compounds of formula II are specifically distinguished by their toxicity to molds, algae, yeast and especially to fungus. They are useful in the formulation of pharmaceutical formulations for local application in the treatment of fungal infections. Because of their fungicidal-fungistatic activity in minute quantities, these compounds are particularly adapted to industrial uses. Those compounds having a terminal iodo group have been found to be especially well suited for use as industrial fungicides. They are, for example, particularly well adapted for use as additives to plastics, paints, cosmetic emulsions and the like and in treating leather, wood, paper, fabrics and the like to prevent deterioration resulting from fungal action in these materials or in surfaces protected by these materials. When used in this way, these compounds have been found to be highly effective at low concentrations, extremely resistant to dimunition of their anti-microbial action and conferring substantially no undesirable properties to the systems treated therewith. The compounds of this invention can be made suitable for anti-microbial application by adding microbicidal amounts to the compositions to be protected or by mixing a microbicidal amount with any conventional carrier, for example, by dissolving in alcohol, acetone or the like.

The suitability and effectiveness of these compounds in treating fabrics is demonstrated by the test results shown in Table V. The tests were conducted by immersing replicate l-inch squares of cotton sheeting in alcohol solutions containing various concentrations of the test compounds. The treated fabrics were air-dried and subjected to petri dish inoculation tests against Aspergillus niger and Chaetomium globosum. For comparative purposes, samples of fabric were treated with a standard fabric fungicide, 2,2-methylenebis(4- chlorophenol). The inoculation materials were examined visually for the presence of growth after a 17- day incubation period and given a numerical rating. The numerical ratings used for this and all subsequent rates described herein have the following designations:

1 No growth on sample.

2. Trace growth on sample.

3. Slight growth on sample.

4. Moderate growth on sample.

5. Heavy growth on sample.

A. Up to 20 mm. zone of inhibition around sample. B. Greater than 20 mm. zone of inhibition around sample. C. Complete inhibition on entire plate.

TABLE VI Fabric Tests Cone. in Compound Alcohol A. niger C. globosum 4-nitrophenyl 3-iodo 2-propynyl ether 0.2 l (C) l 0.1 1 (C) l 0.075% 1 (B) l 0.050% 1 (B) l 0.025% 23 l-Z 0.010% 3 45 0 005% 4 5 Z-nitrophenyl 3-iodo- 2-propynyl ether 0.] l (C) 0.05 l (C) l 4-nitro-l-(3-iodo-2- propynylmereapto)benzene 0.1 l l 0.05 l (A) l 2-nitrophenyl 3-iodol-propynyl ether 0.1 l (B) l 0.05 '72 l (B) l 2,4-dinitrophenyl 3- iodo-2 -propynyl ether 0.1 l (C) l 0.05 l (C) l 2,2'-methylenebis- (4-chlorophenol) 0.5 1 (A) 1 0.2 l-2 l 0.1 3 [-2 0.05 4 4 Control 5 5 The suitability of the novel compounds of formula II for treating leather to prevent against microbial deterioration is demonstrated by the results of the following test. Replicate l-inch squares of vegetable tanned leather were immersed in alcohol solutions containing mineral salt agar media. Results of these tests are illustrated in Table VII.

various concentrations of the compound and were air- TABLE VII dried. Leather samples treated with a standard leather Plastic Tests preservatlve (p-mtrophenol) were tested at the same C b D I M S 011C. Wl. 6X time for comparatlve purposes. The treated samples Compound ofplag'tic Agar agar were sub ected to petr1 dish rnoculatlon tests w1th Aspergillus niger before and after various exposure 4..ni[rophgny| 340d). tests. The exposure tests were as follows. -p py y ether 19% 1 (B) 1 o 0.5% 1 (A) 1 A. Twenty-four hours 1n a circulating an oven at 60 015% 14 1 C S-nitrophenyl 3-iodo- 2- 1 th 0.5% l A l B. Twenty-four hours immerslon in 100 ml. of cold tap water with four complete water changes during p py y pym 05% 2 3 this eriod 2-n1trophenyl 3-1odo- P 2-propynyl ether 0.5% l (A) 2 C. Exposed outdoors on an unsheltered rack for 13 15 2.4-dinitrophenyl 3- da 5 iodo-2-propynyl ether 0.5% l (A) 3 y Control 4 4 The results of the microbiological tests after a 14-day inoculation riod are recorded in Table VI.

p6 Still another of the many antimicroblal appllcatlons TABLE VI in which the novel compounds of formula II have found Leather Tests(A. Niger) particular usefulness in preventing microbial growth Com in Oven and microbially induced degradation in films formed Compound Alcohol Unexposed Aged Leached Weathered from both Oil and Water base paints, Compounds of the present invention when incorporated into an oil paint 4 or a water base paint in an amount between about 0.2

3-1odo-2-propynyl ether 01% 1 NC) 1 percent and 2.0 percent by weight and the resulting 86 i 1 i i paint employed to paint a wood surface, give excellent 3-nitrophenyl S-iodo-Z-propynyl ether control agamst mildew formation when exposed to 0.2 1 (B) 1 (B) 1 (B) rigorous conditions of temperature and humidity. The O1 1 (B) 1 (A) 1 added compound does not adversely affect the shelf life 0.05% 1 (A) 1 (A) 1-2 fth d h l h t ti 4-nitro-l- (3-iodo-2-propynylmercapto)benzenc 0 6 p nor 96s It m y t 6 CO or arac CS 0.2 1 1 and remains effective for an extended period of tlme. 86 1 L 5 The suitability of the compounds of formula II for 2-nitrophenyl 3-iodo-2-propynyl ether use as paint additive to protect against microbiological 8%; 1 2) l (2) 1 deterioration is demonstrated by the results of the folo:05% 1 l l lowing tests. Various concentrations of compounds of 2,4-dinitrophenyl 3- iodo-2-propynyl ether this invention, as well as standard paint additives phengez i 22 L 1 (B) yl mercuric acetate and copper 8-quinolinolate, were (105% 1 (A) 2 milled by hand into a white latex paint. The treated P- p 40 paints were brushed onto both sides of sheets of filter 8:? 2;: L Z paper and air-dried. One sheet of painted paper was cut 005% 3- 4 4 4-5 4-5 into small squares and subjected to petri dish inocula- Comm' 5 5 5 5 tion tests against Pullularia pullulans, Aspergillus oryzae and Aspergillus niger. Another sheet was exposed out- The suitability of the compounds of formula II for ind r f 22 day and then subj cted to the inoculation corporation into plastic compounds so as to inhibit tests. A third sheet was heat-aged in an oven at 60 C. microbial deterioration is demonstrated by the followfor 96 hours, then leached in tap water for 24 hours ing test. Plastic films were cast from solvent solutions prior to the microbiological tests. Finally, the prepared containing a vinyl chloride-acetate resin, a susceptible paints were stored in jars in the laboratory for 2 placticizer and several concentrations of a compound months, then coated onto filter paper to be tested of this invention. The finished films were cut into small against the fungi. Table VIII shows a compilation of the squares and subjected to petri dish inoculation tests test results on all samples after 4-week incubation with Aspergillus flavus on mineral salts and dextroseperiods.

TABLE vrrr Paint tests Cone. by Oven aged wt. (if Unexposed Weathered and leached Storage stability in Compound p r izent P.p. A.0 A.n 1 .1). A.0. A.n P.p. A.o A.n. 1.p A.o. A.n

I 0.25 1 2 2 1 3 2 1(13) 1(A) 2 1(A) 2(A) 1 -l-n1tropl1enyl-iodo-2-propynyl ether 0.50 1(A) 2 .2 1(A) 2(A) .2 MB) 1(A) 2 HA) 2(A) l lit; 15s; 2%; is; lit; 19:; 12s; lllmlylmmurlcacetate 1 R 1(3) 1 0 1 0 1(A) 1 A 1(0) 103) 1(0) HA) -i as lit; 5 1 a s a; i 5 iii; i 5 Control 4 a 5 4 5 2 3 3- 1 3-1 5 5 3-nltr0pl1enyl 3-i0d0-2-pr0pynyl etl1er I. ll 1 1(A) -1-nitro-1-(3-1oil0-2-1u'opynylmereapto) benzene. 1. (J 3-l :z-nitruplmnyl 3-i0du-2-pr0pynyl etherz. 1.0 l (A) 3,-l-tlinitr0ph1u1yl 3-lodo-2-propynyl other. I. 0 1

The suitability of the compounds of formula 11 for use as additives to cosmetic emulsions is demonstrated by the following tests. Cosmetic creams formulated from boiling water emersions with a non-ionic surfac tant were prepared containing various concentrations of compounds of this invention and also with methyl phydroxybenzoate. Jars containing these creams were inoculated with Aspergillus niger and incubated for a 21-day period. Samples were re-inoculated after 7 and 14 days of incubation period. Table 1X shows a summary of the results of these tests.

TABLE IX Cosmetic Emulsion Tests Control 4 The compounds of formula II are particularly noteworthy anti-fungal agents because of their ability to protect oil-water or two-phase systems since most of the conventional microbicides are inactive in these systems. It is a particularly significant property of these compounds that they are effective in the presence of non-ionic surfaces active agents whereas other antifungal agents are not. The compounds are especially valuable for industrial purposes because of their high anti-fungal action in minute quantities and the almost total lack of adverse effects. These compounds are inert to the oils and pigments in paints and, therefore, do not cause discoloration or shorten the shelf life. The small quantities required have no effect on such other properties of paints as brushing and spreading characteristics. These compounds are also inert to the ingredients of conventional cosmetic preparations and, therefore, find a wide application in this area.

In still another aspect this application relates to mixed halonitrophenylpropargyl ethers of the formula ah 1 U wherein m and n are integers from 1 to 4 such that the sum of m and n is not greater than X is halogen preferably chlorine; R is hydrogen or halogen, preferably iodine and Y is a sulfur or an oxygen atom. The compounds of formula III are useful as anti-bacterial/anti-fungal and insecticidal agents. The compounds wherein R is hydrogen are particularly good insecticidal agents especially when used in the formulation of insecticidal compositions in conjunction with carbamate insecticides such as l-napthyl n-methyl carbamate. The compounds wherein R is halogen are notable for their anti-bacterial/anti-fungal properties. They are useful in the treatment of diseases caused by a wide variety of bacteria and fungi. They are also useful as additives in such materials as paints, leather, textiles and other fibrous materials to inhibit the growth of a variety of fungi such as Aspergillus niger and Staphylococcus aurius. Compounds of formula 111 wherein Y is oxygen and m and n are each 1 constitute a preferred group. The compound 2-nitr0-4- chlorophenyl 3-iodopropargyl ether is specifically distinguishable by its inhibitory effect upon the growth of the fungi Aspergillus niger, P. citrinum and Staphylococcus aurius and algae Chlorella vulgaris and v. viridis. The compounds of formula 111 can be utilized in the form of conventional pharmaceutical and insecticidal preparations as described elsewhere in this application. The ethers of formula 111, wherein R is hydrogen like those of formulas 1 and 11, are prepared by condensing an appropriately substituted phenol or thiophenol with bromopropyne. The halogenation of the terminal carbon can be effected by any of the usual procedures for halogenating acetylenic compounds. Alternatively, compounds of formula 111 wherein R is halogen can be obtained directly by condensing a 1,3- dihalopropyne with the appropriately substituted phenol or thiophenol utilizing procedures analogous to those described above.

The starting phenols and thiophenols are products known to the art and prepared by known processes. The manner of preparing the novel compounds of this application will be more fully understood from the following examples which are not to be construed as limitative of the invention. All temperatures are in degrees Centigrade and all melting points are uncorrected.

EXAMPLE 1 Preparation of 2,3-dichlorophenyl 3-iodo-2-propynyl ether To a 2-liter 3-neck round bottom flask equipped with a stirrer and a reflux condenser were charged 200 g. (1.2 moles) of 2,3-dichlorophenol, g. (1.3 moles) of 3-bromopropyne, 186 g. (1.3 moles) of anhydrous potassium carbonate and 1.0 liter of pure acetone. After the reaction mixture was stirred and refluxed for 8 hours, it was cooled to room temperature. The solids were filtered and washed well with 500 ml. of acetone. The solvent was evaporated at 60 in vacuo and the residue was dissolved in 700 ml. of ethanol. The crystals which formed on chilling in an ice-water bath were filtered and washed well with 500 cc. of water. After drying 48 hours in a vacuum desiccator with an hydrous calcium chloride as the desiccant there was obtained 2,3-dichlorophenyl 2propynyl ether, m.p. 47-49 C.

To a 1 liter 3-neck round bottom flask equipped with a stirrer, a dropping funnel and a thermometer were charged 28.8 g. (0.14 moles) of 2,3-dichlorophenyl 2- propynyl ether prepared as above and 300 ml. of pure methanol. To the vigorously stirred solution were added simultaneously 48 g. (0.20 moles) of iodine in small portions and ml. of a 10 percent aqueous sodium hydroxide solution (0.45 moles) dropwise over a period of 15 minutes while the reaction temperature was kept at 2025 by means of an ice-water bath. After stirring for 30 minutes longer at room temperature, the resulting precipitate was filtered and washed well with 200 ml. of water. The solids were dried 24 hours in a vacuum desiccator with anhydrous calcium chloride as the desiccant to give 2,3-dichlorophenyl 3- iodo-2-propynyl ether, m.p. 585 9.

EXAMPLE 2 Preparation of 2,3-dichlorophenyl 3-bromo-2-propynyl ether To a 250 m1. 3-neck round bottom flask equipped with a magnetic stirrer and thermometer was added 50 ml. of a percent aqueous sodium hydroxide solution (0.13 moles). After the solution was cooled to 5 by means of an ice-water bath, 6.4 g. (0.04 moles) of bromine was added. To the cold yellow solution was added a solution of 4.0 g. (0.02 moles) of 2,3- dichlorophenyl 2-propynyl ether in 30 ml. of dioxane. After the reaction mixture was stirred for 45 minutes at -10, the solvents were evaporated at 60 in vacuo.

The solids which formed were slurried with 100 ml. of water, filtered, washed with 200 ml. of water and dried. The crude compound was dissolved in 50 ml. of petroleum ether (B.P. 3060 C.). After cooling the crystals were filtered and air dried to yield 2,3- dichlorophenyl 3-bromo-2-propynyl ether m.p. 68-69.

EXAMPLE 3 Preparation of 2,3-dichlorophenyl 3-chloro-2-propynyl ether To a 500 ml. 3-neck round bottom flask equipped with a stirrer, reflux condenser, dropping funnel and calcium chloride drying tube were added 2.6 g. (0.11 mole) of magnesium turnings and ml. of anhydrous ether. Ethyl bromide (2.5 g., 0.11 mole), dissolved in 20 ml. of anhydrous ether, was added dropwise in order to maintain a gentle reflux and the reaction was then refluxed an additional 15 minutes. 2,3-Dichlorophenyl 2-propynyl ether (20.1 g., 0.10 mole), dissolved in 50 ml. of anhydrous ether, was added dropwise over a period of 15 minutes. After the reaction mixture was refluxed for 5 hours, 19.1 g. (0.10 mole) of ptoluenesulfonyl chloride was added in small portions over a period of 15 minutes and refluxing was continued for 17 hours. The reaction mixture was cooled in an ice bath and acidified with 100 ml. of 3N aqueous hydrochloric acid. The aqueous layer was extracted twice with 150 ml. of ether. The combined ether extracts were washed twice with 100 ml. of water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo at 40. The oily residue was poured onto a column containing 300 g. of silica gel. The column was washed with six 200 ml. portions of petroleum ether (B.P. 3060) and the bulked eluates were evaporated vacuo at 60. The residue was dissolved in 100 ml. of petroleum ether (B.P. 3060). After chilling in an ice bath, the crystals were filtered to give 2,3-

dichlorophenyl 3-chloro-2-propynyl ether, m.p. 6768.

EXAMPLE 4 Preparation of 2,3-dibromophenyl 3-iodo-2-propynyl ether Into a 500 m1., three neck flask, equipped with a mechanical stirrer and a reflux condenser topped with a CaCl tube attached to a gas absorption trap, were placed 100 g. (0.406 moles) of 2-bromo-3-nitrobenzoic acid and 150 ml. of thionyl chloride. The suspension was stirred and heated on a steam bath for 1 hour.

The resulting solution was distilled under reduced pressure, the residue was resuspended twice in 50 ml. of benzene and the solvent was distilled each time to give a dry residue of 2-bromo-3-nitrobenzoylchloride, m.p. 64-67 dec.

108 g. (0.406 moles) of 2-bromo-3- nitrobenzoylchloride, prepared as above was dissolved in 200 cc. of benzene and the solution was poured into a 3-liter, three neck flask containing 1,800 ml. of concentrated ammonium hydroxide. The mixture was stirred mechanically for at least 5 hours. The white precipitate was filtered, pressed, washed well with water and dried to give 2 bromo-3-nitroben2amide, m.p. 170-l72.

A 2-liter, three neck flask provided with a mechanical stirrer, reflux condenser and thermometer was charged with 49 g. (0.2 mole) of 2-bromo-3- nitrobenzamide prepared as above, 96 ml. of a solution, freshly prepared, of sodium hypochlorite containing 16.8 percent of active chlorine (0.2 mole plus 10 percent), 100 ml. of 10 percent KOH solution and 600 ml. of water. The resulting mixture was stirred and heated slowly to reflux. Stirring and refluxing were continued for 15 minutes and then the mixture was allowed to cool to room temperature. The crude, reddish precipitate of 2-bromo-3-nitroaniline was filtered, washed well with water and dried. The product melted at 9092.

Concentrated sulfuric acid (130 ml.) was placed in a 2-liter, three neck flask fitted with a mechanical stirrer and a thermometer and 19 g. (0.275 mole) of solid sodium nitrite was added over a period of 10-15 minutes with stirring. After the addition was completed the temperature was raised to 70 and the mixture was stirred until all the sodium nitrite was dissolved. The solution was cooled to to 5l0 and a solution of 54 g. (0.25 mole) of 2-bromo-3-nitroaniline in 50 ml. of cone. sulfuric acid and 500 ml. of acetic acid was added slowly at room temperature with stirring. After the addition was completed, the solution was stirred for 2 hours. A solution of 50 g. (0.35 mole) of cuprous bromide in 250 ml. of 48 percent hydrobromic acid was prepared in a 2-liter three neck flask, provided with a mechanical stirrer and thermometer and the diazonium solution was added in portions with stirring at room temperature. The reaction mixture was warmed to 60 for 20 minutes. 800 ml. of ice-water was added, the precipitate was filtered, washed with water and dried. The 2,3dibromonitrobenzene melted at 81-82.

31 g. of iron (40 mesh), 200 ml. of water and 3.2 ml. of glacial acetic acid were placed into a 500 ml. three neck flask provided with a stirrer, reflux condenser, thermometer and a dropping funnel. The mixture was refluxed for 30 minutes with stirring. A solution of 28.1 g. (0.1 mole) of 2,3-dibromonitrobenzene in ml. of dioxane was added dropwise to the refluxing mixture. After the addition was completed, stirring and refluxing were continued for one hour. The mixture was cooled to 60 and 21 g. of solid sodium carbonate and 3 g. of Norit added. Stirring was continued for an additional 15 minutes and then it was filtered through a thin layer of l-lyflo. The cake was washed with 350 ml. of

dichloromethane. The dichloromethane was separated from the aqueous phase, washed with water, dried over sodium sulfate and distilled under reduced pressure. The residue, 2,3-dibromoaniline, melted at 4850.

Concentrated sulfuric acid (72 ml.) was placed in a 500 ml. three neck flask fitted with a mechanical stirrer and a thermometer and 7.2 g. (0.104 mole) of solid sodium nitrite was added over a period of 10-15 minutes with stirring. After the addition was completed the temperature was raised to 70 and the mixture was stirred until all the sodium nitrite dissolved. The solution was cooled to room temperature and a solution of 26 g. (0.104 mole) of 2,3-dibromoaniline in 80 ml. of glacial acetic acid was added portionwise with stirring at such a rate that the reaction temperature remained at about 30. After the addition was completed the solution was stirred at room temperature for 2 hours and then at 50 for 30 minutes. The solution was tested with potassium-iodide starch paper for the presence of unreacted sodium nitrite. Solid urea was added until a negative test resulted.

The diazonium compound prepared in this way was added by means of a dropping funnel to a boiling solution of 250 g. of cupric sulfate in 220 ml. of water, contained in a l-liter three neck flask set up for steam distillation. A current of steam was introduced into the boiling solution while the diazonium solution was added dropwise from the central neck. The heating was regulated in such a way that the amount of liquid in the flask remained constant. The distillate was extracted with 3 X 200 ml. of ethyl ether, the ether solution was washed with a small amount of water, dried and distilled under reduced pressure. The 2,3- dibromophenol obtained melted at 5862. Recrystallized from petroleum ether (3060) the product had a melting point of 6465.

A 250 ml. three neck flask, provided with a mechanical stirrer and a reflux condenser was charged with 22.5 g. (0.09 mole) of 2,3-dibromophenol, 14 g. of potassium carbonate, 12 g. (0.09 mole plus percent) of propargyl bromide and 100 m1. of acetone. The mixture was stirred and heated to reflux on a steam bath for 3 hours. The reaction mixture was cooled to room temperature and the precipitate of inorganic salt was filtered. The cake was washed with 20 ml. of acetone and the acetone solution was distilled under reduced pressure to give an almost white residue of 2,3- dibromophenyl 2-propynyl ether melting at 4248.

Recrystallized from petroleum ether (30-60) the product melted at 49-50.

15 g. (0.052 mole) of 2,3-dibromophenyl 2-propynyl ether and 90 ml. of methanol were placed into a 250 ml. three neck flask fitted with a mechanical stirrer, reflux condenser and thermometer. The mixture was stirred at room temperature until solution was complete and 14.4 g. of iodine (0.052 mole plus 10 percent) and 45 ml. of 10 percent NaOl-l solution were added simultaneously. The temperature rose to 40-45 and a white precipitate was formed. The reaction mixture was allowed to cool at room temperature and was filtered. The cake was washed with a solution of 5 percent potassium iodide and then with water. The dry, semi-white 2,3-dibromophenyl 3-iodo-2-propynyl ether melted at 72-77. Recrystallized from ligroin (6090 it melted at 8284.

EXAMPLE 5 Preparation of 2-nitrophenyl 2-propynyl ether A 1 liter three-neck flask, provided with a mechanical stirrer and a reflux condenser was charged with 70 g. (0.5 mole) of 2-nitrophenol, 65.5 g. (0.55 mole) of propargyl bromide, 76 g. (0.55 mole) of potassium carbonate and 500 ml. of acetone. The mixture was stirred and heated to reflux on a steam bath for 10 hours. The

reaction mixture was cooled to room temperature and the precipitate of inorganic salt was filtered ofl. The cake was washed with 50 ml. of acetone and the combined acetone filtrates were distilled under reduced pressure. The semi-white residue of 2-nitrophenyl 2- propynyl ether melted at 72-74 C. Recrystallized from ethanol it melted at 7476 C.

EXAMPLE 6 Preparation of 2-nitropheny1 3-iodo-2-propynyl ether Fifty-three grams (0.3 mole) of Z-nitrophenyl 2- propynyl ether and 1,000 ml. of methanol were placed into a 2 liter three-neck flask fitted with a mechanical stirrer, reflux condenser and thermometer. The mixture was stirred at room temperature until solution was complete and 84 g. (0.33 mole) of iodine and 300 ml. of 10 percent sodium hydroxide solution were added simultaneously. The temperature rose to -45 C. and a white precipitate was formed. The reaction temperature was allowed to cool to room temperature and the mixture was filtered. The cake was washed with a solution of 5 percent potassium iodide and then with water. The dry, almost white 2-nitrophenyl 3-iodo-2- propynyl ether melted at 94-96 C. Recrystallized from ethanol it melted at 96-98 C.

EXAMPLE 7 Preparation of 3-nitrophenyl 2-propynyl ether A 1 liter three-neck flask, provided with a mechanical stirrer and a reflux condenser was charged with 70 g. (0.5 mole) of 3-nitrophenol, 65.5 g. (0.55 mole) of propargyl bromide, 76 g. (0.55 mole) of potassium carbonate and 500 ml. of acetone. The mixture was stirred the precipitate of inorganic salt was filtered off. The

cake was washed with 50 ml. of acetone and the combined acetone filtrates were distilled under reduced pressure. The almost white residue of 3-nitrophenyl 2- propynyl ether melted at -72 C. Recrystallized from ethanol it melted at 6769 C.

EXAMPLE 8 Preparation of 3-nitrophenyl 3-iodo-2-propynyl ether Fifty-three grams (0.3 mole) of 3-nitrophenyl 2- propynyl ether and 1,000 ml. of methanol were placed into a 2 liter three-neck flask fitted with a mechanical stirrer, reflux condenser and thermometer. The mixture was stirred at room temperature until solution was complete and 84 g. (0.33 mole of iodine and 300 ml. of 10 percent sodium hydroxide solution were added simultaneously. The temperature rose to 40-45 C. and a white precipitate was formed. The reaction temperature was allowed to cool to room temperature and the mixture was filtered. The cake was washed with a solution of 5 percent potassium iodide and then with water. The dry, semi-white 3-nitrophenyl 3-iodo-2- propynyl ether melted at 8587 C. Recrystallized from ligroin (6090), it melted at 88-90 C.

EXAMPLE 9 Preparation of 4-nitrophenyl 2-propynyl ether To a 1 liter 3-neck round bottom flask equipped with a stirrer and a reflux condenser were charged 70.0 g. (0.50 moles) of 4-nitrophenol, 65.5 g. (0.55 moles) of 3-bromopropyne, 76.2 g. (0.55 moles) of anhydrous potassium carbonate and 500 ml. of pure acetone. After the reaction mixture was stirred and refluxed for 8 hours, it was cooled to room temperature. The solids were filtered and washed well with 500 ml. of acetone. The solvent was evaporated at 60 in vacuo and the residue was dissolved in 700 ml. of ethanol. The crystals which formed on chilling in an ice-water bath were filtered and washed well with 500 cc. of water. After drying 48 hours in a vacuum desiccator with an hydrous calcium chloride as the desiccant there was obtained 4-nitrophenyl Z-propynyl ether, m.p. 114-11 6 C.

EXAMPLE l Preparation of 4-nitrophenyl 3-iodo-2-propynyl ether To a 1 liter 3-neck round bottom flask equipped with a stirrer, a dropping funnel, a reflux condenser and a thermometer were charged 17.7 g. (0.10 moles) of 4- nitrophenyl 2-propynyl ether prepared as above and 500 cc. of pure methanol. The mixture was stirred and refluxed until all the solids were dissolved. To the vigorously stirred solution, which was cooled to 4550 C., were added simultaneously 28 g. (0.11 moles) of iodine in small portions and 100 ml. of a 10 percent aqueous sodium hydroxide solution (0.25 moles) dropwise over a period of minutes while the reaction temperature was kept below 50 C. After stirring for 30 minutes longer at room temperature, the reaction mixture was cooled in an ice-water bath. The solids were filtered, washed well with 200 ml. of water and dried 24 hours in a vacuum desiccator with anhydrous calcium chloride as the desiccant to give 4-nitrophenyl 3-iodo- 2-propynyl ether, m.p. l87-l 88 C.

EXAMPLE 1 1 Preparation of 2,4-dinitrophenyl 2-propynyl ether A 2 liter three-neck flask, equipped with a mechanical stirrer and a reflux condenser was charged with 93 g. (0.5 mole) of 2,4-dinitrophenol 65.5 g. (0.55 mole) of propargyl bromide, 44 g. of solid sodium hydroxide and 700 ml. of water. The mixture was stirred and heated on a steam bath for 24 hours and then it was acidified with dilute (lzl) hydrochloric acid and allowed to cool to room temperature. The precipitate was filtered and washed well with water. The dry reaction product weighed 102 g. and melted at 7582 C. The erude product was suspended in 350 ml. of ethyl acetate. The suspension was washed with 2 X 200 of a 5 percent sodium hydroxide solution, then with water and the organic layer was dried over sodium sulfate and distilled under reduced pressure. The crude residue of 2,4'dinitrophenyl 2-propynyl ether melted at 84-88 C. Recrystallized from ethanol it melted at 98-l 00 C.

EXAMPLE 12 Preparation of 2,4-dinitrophenyl 3-iodo-2-propynyl ether Sixty-six grams (0.3 mole) of 2,4-dinitrophenyl-2- propynyl ether and 1,200 ml. of methanol were placed into a 2 liter three-neck flask fitted with a mechanical stirrer, reflux condenser and thermometer. The mixture was stirred at 3540 C. until solution was complete and 84 g. (0.33 mole) of iodine and 300 ml. of 10 percent sodium hydroxide solution were added simultaneously. The temperature rose to 5055 C. and a white precipitate was formed. The reaction temperature was allowed to cool to room temperature and the reaction mixture was filtered. The cake was washed with a solution of 5 percent potassium iodide and then with water. The dry, semi-white 2,4-dinitrophenyl 3- iodo-2-propynyl ether thus obtained melted at -86 C. Recrystallized from ethanol it melted at 112-l 14 C.

EXAMPLE 13 2,6-Dinitrophenyl Z-propynyl ether A 1 liter three-neck flask, provided with a mechanical stirrer and a reflux condenser, was charged with 37 g. (0.2 mole) of 2,6-dinitrophenol, 29 g. (0.24 mole) of propargyl bromide, 24 g. (0.24 mole) of potassium bicarbonate and 600 ml. of acetonitrile. The mixture was stirred and heated to reflux on a steam bath for 24 hours. The reaction mixture was cooled to room temperature and the precipitate of inorganic salt was filtered. The cake was washed with 20 ml. of acetonitrile and the combined acetonitrile filtrates were distilled under reduced pressure. The almost white residue of 2,6-dinitrophenol 2-propynyl ether melted at 5862.

EXAMPLE l4 2,6-Dinitrophenyl 3-iodo-2-propynyl ether Twenty-two grams (0.1 mole) of 2,6-dinitrophenyl 2- propynyl ether and 300 ml. of methanol were placed into a 1 liter three-neck flask provided with a mechanical stirrer, reflux condenser and thermometer. The mixture was stirred at 3035 until solution was complete and 28 g. (0.11 mole) of iodine and 100 ml. of 10 percent sodium hydroxide solution were then added simultaneously. The temperature rose to 40-45 and a white precipitate was formed. The reaction mixture was allowed to cool to room temperature and was filtered. The cake was washed with a solution of 5 percent potassium iodide and then with water. The dry, 2,6-dinitrophenyl 3-iodo-2-propynyl ether melted at 94.

EXAMPLE 15 Preparation of 4-chloro-2-nitrophenyl 2-propynyl ether A 2 liter three-neck flask fitted with a mechanical stirrer and a reflux condenser was charged with 87 g. (0.5 mole) of 4-chloro-2-nitrophenol, 65.5 (0.55 mole) of propargyl bromide, 44 g. of solid sodium hydroxide and 700 ml. of water. The mixture was stirred and heated on a steam bath for 24 hours. The reaction mixture was acidified with dilute (1:1) hydrochloric acid and allowed to cool to room temperature. The precipitate was filtered and washed well with water. The crude product was suspended in 350 ml. of ethyl acetate. The suspension was washed with 2 X 200 of a percent solution of sodium hydroxide, then with 2 X 100 of distilled water, and the organic layer was dried over sodium sulfate and distilled under reduced pressure. The crude residue of 4-chloro-2-nitrophenyl 2- propynyl ether melted at 75-85. Recrystallized from ethanol it melted at 85-86.

EXAMPLE 16 Preparation of 2-nitro-4-chlorophenol 3-iodo-2- propynyl ether Sixty-four grams (0.3 mole) of 4-chloro-2-nitrophenyl 2-propynyl ether and 1,200 ml. of methanol were placed into a 2 liter three-neck flask fitted with a mechanical stirrer, reflux condenser and thermometer. The mixture was stirred at 35-40 until solution was completed and 84 g. (0.33 mole) of iodine and 300 ml. of percent sodium hydroxide solution were added simultaneously. The temperature rose to 50-55 and a white precipitate was formed. The reaction temperature was allowed to cool to room temperature and the mixture was filtered. The cake was washed with a solution of 5 percent potassium iodide and then with water. The dry 4-chloro-2-nitrophenyl 3-iodo-2-propynyl ether melted at 1 l0-1 Recrystallized from ethanol it melted at l 16-1 17.

EXAMPLE 17 Preparation of 4-chloro-6-iodo-2-nitrophenyl 2- propynyl ether A 500 ml. three neck flask, fitted with a mechanical stirrer and a reflux condenser, was charged with 18.5 g. (0.062 mole) of 4-chloro-6-iodo-2-nitrophenol, 8.2 g. (0.0067 mole) of propargyl bromide, 9.2 g. (0.067 mole) of potassium carbonate and 200 ml. of acetone. The mixture was stirred and heated to reflux on a steam bath for 30 hours. The reaction mixture was cooled to room temperature and the precipitate of inorganic salt was filtered and the acetone solution distilled under reduced pressure. The almost white residue of 4- chloro-6-iodo-2-nitrophenyl 2-propynyl ether melted at 8186. Recrystallized from ligroin it melted at 9193.

EXAMPLE 18 Preparation of 4-chloro-6-iodo-2-nitrophenyl 3-iodo-2- propynyl ether Fifteen grams (0.644 mole) of 4-chloro-6-iodo-2- nitrophenyl ether and 170 ml. of methanol were placed in a 500 ml. three-neck flask provided with a mechanical stirrer and thermometer. The mixture was stirred at 30-35 until solution was complete and 13.7 g. (0.05 mole) of iodine and 40 ml. of 10 percent sodium hydroxide solution were added simultaneously. The temperature rose to 40-45 and a white precipitate was formed. The reaction mixture was allowed to cool to room temperature and then filtered. The cake was washed with a solution of 5 percent potassium iodide and then with water. The dry semi-white 4-ch1oro-6- iodo-2-nitrophenyl 3-iodo-7-propynyl ether recrystallized from ethanol melted at 1 15l 16.

EXAMPLE 19 2,3-Dichlorol 3-iodo-2-propynylmercapto)benzene To a 500 ml. 3-neck round bottom flask equipped with a stirrer and a dropping funnel were charged 40.5 g. (0.25 mole) of 2,3-dichloroaniline and 100 ml. of 6N aqueous hydrochloric acid. To the chilled solution (05) was added dropwise, a solution of 18.7 g (0.27 mole) of sodium nitrite in 40 ml. of water over a period of 30 minutes. After stirring for an additional 30 minutes at 0-5, the reaction was allowed to warm to 20. The diazonium salt solution was added dropwise to a solution of 46 g. (0.29 mole) of potassium ethyl xanthate in 100 ml. of water over a period of 30 minutes while maintaining a reaction temperature of 40-50. After the addition was complete the reaction was heated on a steam bath for 1 hour. The reaction was then chilled in an ice bath and extracted three times with 200 ml. of ether. The ether extracts were washed once with 200 ml. of water, dried over anhydrous sodium sulfate, filtered and evaporated at 40 in vacuo. The residue was dissolved in 150 ml. of hot ethanol and transferred to a 500 ml. 3-neck round bottom flask equipped with a stirrer and a reflux condenser. To the solution was added g. (1.4 moles) of potassium hydroxide in small portions over a period of 15 minutes. After the reaction was refluxed for 10 hours, it was chilled with an ice bath and acidified by adding dropwise 150 ml. of an aqueous solution of hydrochloric acid. The solution was extracted three times with 200 ml. of ether. The ether extracts were combined and washed three times with ml. of water, dried over anhydrous sodium sulfate, filtered and evaporated at 40 in vacuo to yield 2,3- dichlorothiophenol which was used without further purification.

To a 500 ml. 3-neck round bottom flask equipped with a stirrer, a dropping funnel and a thermometer were charged 17.1 g. (0.144 mole) of 3-bromopropyne and 50 ml. of pure methanol. To the vigorously stirred solution, which was cooled to 1520, were added simultaneously 48 g. (0.19 mole) of iodine in small portions and 180 ml. of a 10 percent aqueous sodium hydroxide solution (0.44 mole) dropwise over a period of 15 minutes while the reaction temperature was kept at 20 C. After stirring for 1 hour longer at room temperature the reaction mixture was diluted with 100 ml. of ether and 50 ml. of water. The aqueous layer was separated and extracted three times with 75 ml. portions of ether. The combined ether extracts were washed once with 100 ml. of water, dried over anhydrous sodium sulfate and evaporated to yield 1-iodo- 3-bromopropyne.

To a 250 ml. 3-neck round bottom flask equipped with a stirrer and a reflux condenser were charged 8.9 g. (0.05 mole) of 2,3-dichlorothiophenol, prepared as above, 14.7 g. (0.06 mole) of l-iodo-3-bromopropyne, prepared as above, 8.3 g. (0.06 mole) of potassium carbonate and ml. of acetone. After the reaction mixture was stirred and refluxed for 8 hours, the solids were filtered and the filtrate was evaporated in vacuo at 60. The residue was taken up in 250 ml. of petroleum ether (30-60) and chromatographed on 150 g. of silica gel. After taking a total of 1 liter of petroleum ether (30-60) eluates which were discarded, the column was eluted with eight 200 ml. portions of a mixture of benzene l petroleum ether which was pooled and evaporated. The residue was crystallized from 50 ml. of petroleum ether 30-60) to give 2,3-dichlorol-(3-iodo-2-propynylmercapto)benzene, m.p. 72-74.

EXAMPLE 20 4-Nitrol 3-iodo-2-propynylmercapto )benzene To a 1 liter three-neck round bottom flask equipped with a stirrer and a reflux condenser were charged 23 g. (0.15 mole) of p-nitrothiophenol, 55 g. (0.22 mole) of l-iodo-3bromopropyne prepared as in Example 19, 27.9 g. (0.20 mole) of potassium carbonate and 400 ml. of acetone. After the reaction mixture was stirred and refluxed for 8 hours, it was cooled to room temperature. The solids were slurried in 500 ml. of petroleum ether (B.P. 30-60), filtered and washed with 500 ml. of petroleum ether. The solids were dissolved in 400 ml. of hot ethanol and the insolubles were filtered. After the solution was chilled, the crystals were filtered to obtain 4-nitro-l-(3-iodo-2-propynylrnercapto)benzene, M.P. l74175 C.

EXAMPLE 21 Preparation of 4-nitrol 2- propynylmercapto)benzene To a 500 ml. 3-neck round bottom flask equipped with a stirrer and dropping funnel were charged 31 g. (0.2 mole) of 4-nitrothiophenol and 84 ml. (0.21 mole) of a 10 percent aqueous sodium hydroxide solution. To the stirred solution was added dropwise 26 g. (0.22 mole) of propargyl bromide over a period of minutes keeping the reaction temperature between 25 and 30 C. After stirring 1 hour at room temperature the precipitate was filtered, washed with 200 ml. of water and dried in a vacuum oven at 50 C. to yield 4- nitro-l-(2-propynylmercapto)benzene, m.p. 95-97 C.

EXAMPLE 22 Preparation of 2-nitro-4-chloro- 1 -(2- propynylmercapto)benzene To a 500 ml. 3-neck round bottom flask equipped with a stirrer and dropping funnel were charged g. (0.1 mole) of 2-nitro-4-chlorothiophenol and 55ml. (0.14 mole) of a 10 percent aqueous sodium hydroxide solution. To the stirred solution was added dropwise 13 g. (0.11 mole) of propargyl bromide over a period of 15 minutes keeping the reaction temperature between 25 and C. After stirring 1 hour at room temperature the precipitate was filtered, washed with 200 ml. of water and dried in a vacuum oven at 60 to yield 2- nitro-4-chloro-l-(Z-propynyl-mercapto)benzene, m.p. 1 34-] 36 C.

EXAMPLE 23 Preparation of 2-bromo-3-chlorophenyl 2-propynyl ether and 2-bromo-3-chlorophenyl 3-iodo-2-propynyl ether Concentrated sulfuric acid (130 ml.) was placed in a 2-liter, three neck flask fitted with a mechanical stirrer and a thermometer and 19 g. (0.275 mole) of solid sodium nitrite was added over a period of 10-15 minutes with stirring. After the addition was completed the temperature was raised to and the mixture was stirred until all the sodium nitrite was dissolved. The solution was cooled to 510 and a solution of 54 g. (0.25 mole) of 2-bromo-3-nitroaniline prepared as in Example 4 in 50 ml. of conc. sulfuric acid and 500 ml. of acetic acid was added slowly at room temperature with stirring. After the addition was completed, the solution was stirred for 2 hours. A solution of 34 g. (0.35 mole) of cuprous chloride in 250 ml. of conc. hydrochloric acid was prepared in a stirred 2-liter three neck flask at room temperature. The reaction mixture was held at 60 for 20 minutes, 800 ml. of ice-water was added and the precipitate was filtered, washed with water and dried. The crude 2-bromo-3- chloronitrobenzene, recrystallized from 300 cc. of petroleum ether (3060) had a melting point of 40-43.

31 g. of iron, 40 mesh, 200 ml. of water and 3.2 ml. of glacial acetic acid were placed into a 500 ml. three neck flask provided with a stirrer, reflux condenser, thermometer and a dropping funnel. The mixture was refluxed for 30 minutes with stirring. A solution of 23.6 g. (0.1 mole) of 2-bromo-3-chloronitrobenzene in 120 ml. of dioxane was added dropwise to the refluxing mixture. After the addition was completed, stirring and refluxing were continued for 1 hour. The mixture was cooled to 60 and 21 g. of solid sodium carbonate and 3 g. of Norit were added. Stirring was continued for an additional 15 minutes and then the mixture was filtered through a thin layer of Hyflo. The cake was washed with 350 ml. of dichloromethane. The dichloromethane was separated from the aqueous phase, washed with water, dried over sodium sulfate and distilled under reduced pressure to give an oily residue of 2 -bromo-3-chloroaniline, b.p. 95-98l0.04

Concentrated sulfuric acid (72 ml.) was placed in a l-liter three neck flask fitted with a mechanical stirrer and a thermometer and 7.2 g. (0.50 mole) of solid sodium nitrite was added over a period of 10-15 minutes. After the addition was completed the temperature was raised to 70 and the mixture was stirred until all the sodium nitrite dissolved. The solution was cooled to room temperature and a solution of 20.6 g. (0.10 mole) of 2-bromo-3-chloroaniline in ml. of glacial acetic acid was added portionwise with stirring at such a rate that the reaction temperature remained at about 30. After the addition was completed, the solution was stirred at room temperature for 2 hours and then at 50 for 30 minutes. The solution was tested with potassiumiodide starch paper for the presence of unreacted sodium nitrite and, because a positive test was obtained, solid urea was added until a negative test was obtained.

The diazonium compound prepared above was added by means of a dropping funnel to a boiling solution of 350 g. of cupric sulfate in 220 ml. of water, contained in a l-liter three neck flask set up for steam distillation. A current of steam was introduced into the boiling solution while the diazonium solution was added dropwise from the middle neck. The heating was regulated in such a way that the amount of liquid in the flask remained constant. The distillate was extracted with 3 X 150 ml. of ethyl ether, the ether solution was washed with a small amount of water, dried and distilled under reduced pressure. The 2-bromo-3- chlorophenol was obtained as an oil. A small amount, crystallized from petroleum ether (30-65), melted at 4547.

A 250 ml. three neck flask, provided with a mechanical stirrer and a reflux condenser, was charged with 20.7 g. (0.1 mole) of 2-bromo-3-chlorophenol, 14 g. of potassium carbonate, 13.2 g. of 0.1 1 mole of propargyl bromide and 100 ml. of acetone. The mixture was stirred and heated to reflux on a steam bath for 8 hours. The reaction mixture was cooled to room temperature and the precipitate of inorganic salt was filtered. The cake was washed with 20 ml. of acetone and the acetone solution was distilled under reduced pressure. The oily residue of 2-bromo-3-chlorophenyl 2-pr0pynyl ether distilled at 7210.04 mm.

13 g. (0.1 mole of 2-bromo-3-chlorophenyl 2-propynyl ether and 100 ml. of methanol were placed into a 250 ml. three neck flask fitted with a mechanical stirrer, reflux condenser and thermometer. The mixture was stirred at room temperature until solution was complete and 30.8 g. (0.11 mole) of iodine and 90 ml. of 10 percent NaOH solution were added simultaneously. The temperature rose to 4045 and a white precipitate was formed. The reaction mixture was allowed to cool to room temperature and was filtered. The cake was washed with a solution of percent potassium iodide and then with water. The dry, offwhite 2-bromo-3-chlorophenyl 3-iodo-2-propynyl ether melted at 60-68. A small sample recrystallized from ligroin (60-90) melted at 80-82.

EXAMPLE 24 Preparation of 2-nitro-4-chloro- 1 -(2- propynylmercapto)benzene and 4-chloro-2-nitrol -(3- iodo-2propynylmercapto)benzene To a 500 ml. 3-neck round bottom flask equipped with a stirrer and dropping funnel were charged 20 g. (0.1 mole) of 2-nitro-4-chlorothiophenol and 55 ml. (0.14 mole) of a percent aqueous sodium hydroxide solution. To the stirred solution was added dropwise 13 g. (0.11 mole) of propargyl bromide over a period of 15 minutes keeping the reaction temperature between 25 and 30 C. After stirring 1 hour at room temperature the precipitate was filtered, washed with 200 ml. of water and dried in a vacuum oven at 60 to yield 2- nitro-4 chlorol 2-propynylmercapto)benzene, m.p. 134-136 C.

Into a 250 ml. 3-neck round bottom flask equipped with a stirrer, thermometer and dropping funnel were charged 8 g. (0.08 mole) of cuprous chloride, g. (0.21 mole) of ammonium carbonate and 40 ml. of water. The mixture was stirred and heated to 50 in order to dissolve the solids. To the warm solution was added dropwise a solution of 9.1 g. (0.04 mole) of 4- chloro-2-nitro- 1 2-propynylmercapto )benzene in 40 ml. of dioxane over a period of 15 minutes. After the reaction mixture was stirred vigorously for 30 minutes, the precipitate was filtered, washed with 200 ml. of water and transferred with 200 ml. of water to a 500 ml. 3-neck round bottom flask equipped with a stirrer. To the slurry was added at once a solution of 10 g. (0.04 mole) of iodine, 10 g. (0.06 mole) of potassium iodide and 30 ml. of water. After the reaction mixture was stirred for 1 hour, the solids were filtered and washed four times with 150 ml. of water. The remaining solids were washed three times with 200 ml. of hot benzene. The benzene extracts were evaporated at 60 under reduced pressure. The residue was slurried with 200 ml. of ethanol and filtered to yield 4-chlor0-2- nitro- 1 3-iodo-2-propynylmercapto)benzene, m.p. l67168.

EXAMPLE 25 Preparation of 2,4-dinitro-1-(2- propynylmercapto )benzene and 2,4-dinitro l-(3-iodo 2-propynylmercapto)benzene To a 500 ml. 3-neck round bottom flask equipped with a stirrer and dropping funnel were charged 40.8 g. (0.2 mole) of 2,4-dinitrothiophenol and 96 ml. of a 10 percent aqueous solution of sodium hydroxide. To the stirred solution was added dropwise 26 g. (0.22 mole) of 3-bromopropyne over a period of 15 minutes keeping the reaction temperature between 25 and 30. After stirring 1 hour at room temperature the precipitate was filtered, washed with 200 ml. of water. The solids were crystallized from 100 ml. of benzene to yield 2,4-dinitrol 2-propynylmercapto)-benzene, m.p. 122-124.

To a 250 ml. 3-neck round bottom flask equipped with a stirrer, thermometer and a dropping funnel were charged 8 g, (0.08 mole) of cuprous chloride, 20 g. (0.21 mole) of ammonium carbonate and 40 ml. of water. The mixture was stirred and heated to 50 in order to dissolve the solids. To the warm solution was added dropwise a solution of 9.6 g. (0.04 mole) of 2,4- dinitro-1-( 2-propynylmercapto)benzene in 50 ml. of dioxane over a period of 15 minutes. After the reaction mixture was stirred vigorously for 30 minutes, the precipitate was filtered, washed with 200 ml. of water and transferred with 200 ml. of water to a 500 ml. 3- neck round bottom flask equipped with a stirrer. To the slurry was added at once a solution of 10 g. (0.04 mole) of iodine, 10 g. (0.06 mole) of potassium iodide and 30 ml. of water. After the reaction mixture was stirred for 1 hour the solids were filtered and washed four times with m1. of water. The remaining solids were washed three times with 200 ml. of hot benzene. The benzene extracts were evaporated at 60 under reduced pressure. The residue was slurried with 200 ml. of ethanol and filtered to yield 2,4-dinitro-l-(3-iodo-2- propynylmercapto)benzene.

Alternatively, 2,4-dinitro- 1 3-iodo-2-propynylmercapto)-benzene was prepared by the following procedure:

To a 250 ml. 3-neck round bottom flask equipped with a stirrer and a reflux condenser were charged 10.2

23 24 g. of 2.3-dinitrothiophenol, 14.7 g. (0.06 mole) of lcrystallized to give 2,3-dinitro-l-(3-i0d0-2-propynyliodo-3-bromopropyne, prepared as in Example 19, 8.3 mercapto)benzene. g. (0.06 mole) of potassium carbonate and 150 ml. of What s C med iS acetone. After the reaction mixture was stirred and L The compound A' P Y 'P PY' refluxed for 8 hours, the solids were filtered and the fil- Y ether- I trate was evaporated in vacuo at 60. The residue was 

